Cardiac Arrythmias Flashcards
ECG wave
- P wave - Representative of Atrial depolarisation > preceeds the QRS complex
- PR interval - at the start of the P wave and ends at the beginning of the Q wave. Time taken for electrical activity to move between the atria and the ventricles.
- QRS complex - Representative of Ventricular depolarisation > three closely related waves on the ECG (Q, R and S waves)
- ST segment - Starts at the end of the S wave and ends at start of T wave. It represnets time between depolarisation and repolarisation of the ventricles.
- T wave - Representative of Ventricular repolarisation that appears after the QRS complex
- RR interval - Begins at peak of 1 R wave and ends at the peak of the next R wave; represents ime between 2 QRS complexes
-QT interval - Begins at start of QRS and finishes at the end of the T wave; represents time taken for the ventricles to depolarise then repolarise
+ Differences in recordings of ECG with LQT and SQT are complex as there are variable changes observed in patients. Patterns can be observed, but there will be exceptions.
Cardiac action potential - Ventricular myocytes
Typical myocyte ap:
- Resting negative membrane potentials set by K+ channels open
- Intercollated disks and electrical signals pass on (neighbouring cells) leading to depolarisation and when threshold is reached, opening of Nav
- at peak, sodium channels close and calcium channels open (Cav) > allows ca to enter the cell (activate slightly slower process than Nav; only opening when Nav closes)
- Plateau phase caused by opening of Cav
- Closing of Cav and opening of Kv leading to repolarisation.
Long QT
*Timothy syndrome can be classified, but are sometimes put in a seperate classification.
A prolonged QT interval caused by abnormal ventricular repolarisation. They are associated with malignant ventricular arrhythmias.
- >440msec
Short QT / Brugada Syndrome
- Extremely rare disease characterized by abnormally short QTc through accelerated reploarisation
- <360msec for male, <370ms female
-SQTS1 through 5
*SQTS4 and STQS5 are loss of function mutations
ECG: Subtle changes
- Accentuated J wave
- ST segment elevation > sits higher on actual recording, T wave kicks in earlier so it doesnt have the time to go down to WT levels
Timothy Syndrome (Long QT)
- Multiple organs affected: Heart, skin, eyes, teeth, brain
- Congenital heart disease, arrhythmias, syndactyly, immune deficiency, autism
- Phentoypes of a round face, flat nasal bridge, thin upper lip, webbed digits.
PROLONGED QT interval
Calcium channel molecular families
- 24 TMs in 4 blocks of 6 in channel, 4 v sensing regions (identical to Nav in basics, historical link in evolution?)
- Range of beta sub units which regulate > modify properites of Cav
Multiple families of Cav:
CHANNEL TYPE: L, N, P/Q, R or T > different sensitivity to membrane potential
L is 1.1-1.4
N, P, Q and R are Cav2
T is Cav3
Cav1.2 channel
- 12 alternative splicing loci > there are 42 different splice variants. Protein that is produced can have slighlty different amino acids seq hence 42.
- Found at T tubules close to sarcoplasmic reticulum
- WT > depolarisation and activation of Cav allows current to move in, inactivation (same cycle as Nav) > mediated by Voltage dependant inactivation and Ca2+ dependent inactivation (where Ca feeds back into the channel itself to inactivate). Beta subunit has a role in inactivation.
Ventricular Tachycardia
- Uncontrolled ventricular depolarisation/repolarisation leading to sudden cardiac failure and further death
- 17 children studied in 1 paper: 10 died, mean age is 21/2 yrs, 12/17 experienced life threatening arrhythmias, survivors had motor and cognitive impairment
+ Association between Cav1.2 and other conditions observed in Timothy Syndrome due to long lasting impairments from life threatening arrhythmias.
New splice form of Cav1.2
Is a mutation, but is technically a new splice variant is observed in all 13 patients examined.
Glycine to Arganine , G406R > end of 6th TM of 1st set of 6 (this glycine is conserved in Cav in humans and other species > indication that its important for ion channel function)
Impact of G406R:
- Whole cell recordings: Shows slowing of inactivation and amount of inactivation is LESS at 1 time point compared to WT.
- Looking at specific time point, checked relative Ca current to see whats left at each potential. Compared to WT, G406R shows less inactivation
- Small impact on Ca dependent inactivation
- LARGE impact on VOLTAGE dependent inactivation
+ Positive potentials show relief of inactivation from Ca dependency > not as effective at high +ve currents.
Study on G406R VOLTAGE DEPENDENT activation - How to get rid of Ca dependent?
- Calcium is the charge carrier in EC solution > Ca then feeds back into channel to inactivate
- For Voltage only, take Ca out of solution and replace with BARIUM Ba2+
- As Ba is a molecule which is a divalent cation, it works through pore like Calcium does > Ba replaces and works as a replacement, however Barium does not feed back and therefore will only see voltage dependent inactivation.
G406R and Voltage dependent inactivation
- Activation is normal, Inactivation is virtually gone
- If Cav1.2 channels are in ventricular myocytes, they will inactivate more slowly, longer plateau and therefore delaying repolarisation leading to the long QT symptoms in Timothy Syndrome.
Impact on heart with the Cav1.2 splice variant
+ In patients, not al their Cav1.2 has the variation at the particular position as its a SPLICE VARIANT. Depending on splice variant construction, the modelling predicted an individual able to produce the novel splice variant of 1 of the Cav1.2 genes would have 11.5% of all the Cav1.2 subunits. Small effect on Calcium current expected.
+ Actually saw a LARGE IMPACT > 17% longer cardiac action potentials
- After depolarisation, theres a delay in repolarisation with those who are heterozygous for the novel splice variant
SQTS4
- Loss of function short QT syndrome mutation on the CACNA1C gene. Effects Calcium current
SQTS5
- Loss of function short QT syndrome mutation on the CACNB2b gene. Effects Calcium current
- Effects BETA SUBUNIT loss of function, hence effects Cav1.2 due to loss of regulatory beta subunit
Impacts of mutations - Overexpressed and Ca currents measured
WT: Set potential, activation and increase in inward current, Ca and V dependent inactivation
- A39V in CACNA1C (Alanine for valine):
- Currents are much smaller at activation
- No impairement of inactivation seen
Location: Perinuclear channels, number of channels is smaller - G490R in CACNA1C (Glycine for arganine):
- Small increase at activation, SIGNIFICANTLY
- no issue with inactivation
Location: similar to WT, mutations that effect gating - S481L in CACNB2b (Serine for leucine):
- Small inward currents, SIGNIFICANTLY
- no issue with inactivation
Location: similar to WT, mutations that effect gating
+If Cav channels arent opening, plateau phase will not be as long, hence short QTc. Smaller currents coming through all mutation variants
+ If plateau phase cannot be maintained steadily, repolarisation happens quicker.
Most mutations studied tend to effect gating > don’t open as they should do, hence small currents as Po is lower.
